Pembrolizumab/Lenvatinib With and Without Healthy Donor FMT (hdFMT) in Relapsed/ Refractory (R/R) Melanoma

NCT06030037 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: HCC 22-077
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

In this is a randomized phase II study the addition of hd-FMT (healthy donor fecal-microbiota transplant) to pembrolizumab /lenvatinib in PD-1 R/R melanoma will be evaluated over a 104-week period in patients with anti-PD-1 R/R disease. Patients with PD-1 refractory advanced melanoma are eligible to enroll, excluding patients with prior lenvatinib (or other TKI) exposure. Intestinal microbiome composition mediates response to anti-PD-1 by affecting systemic inflammatory tone.

Conditions

PD-1 Refractory Advanced Melanoma

Keywords

CD8+ T-cells; CD8+ effector T cells; FoxP3+ regulatory T-cells (T-regs); hdFMT (healthy donor Fecal-Microbiota Transplant)

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR) per RECIST v1.1

  The proportion of patients with objective response to treatment assessed using Response Evaluation Criteria in Solid Tumors v1.1 (RECIST). Per RECIST v1.1: Complete Response (CR): disappearance of all target lesions. Any pathological lymph nodes (target or nontarget) with reduction in short axis to \<10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

  Up to 5 years

Secondary Outcomes (9)

• Incidence of Adverse Events Related to Treatment

  Up to 5 years

• Objective Response Rate (ORR) per iRECIST

  Up to 5 years

• 6-month Progression-free Survival

  Up to 6 months

• 1-year Progression-free Survival (PFS)

  Up to 1 year

• 2-year Progression-free Survival (PFS)

  Up to 2 years

Study Arms (2)

hdFMT + pembrolizumab/lenvatinib (Arm A)

EXPERIMENTAL

* Pembrolizumab will be administered at 200 mg every 3 weeks (Q3W) as a 30-minute IV infusion (treatment intervals may be increased due to toxicity as described). * Lenvatinib will be administered at 20 mg daily. * hdFMT (induction) will be administered at C1D1 and C4D1 via colonoscopy or oral capsules * hdFMT (maintenance) will be repeated every 9 weeks starting with C4D1 via sigmodoscopy or oral capsules

Biological: Healthy Donor Fecal Microbiota Transplantation (hdFMT); Drug: Pembrolizumab; Drug: Lenvatinib

pembrolizumab/lenvatinib (Arm B)

ACTIVE COMPARATOR

* Pembrolizumab will be administered at 200 mg every 3 weeks (Q3W) as a 30-minute IV infusion (treatment intervals may be increased due to toxicity as described). * Lenvatinib will be administered at 20 mg daily.

Drug: Pembrolizumab; Drug: Lenvatinib

Interventions

Healthy Donor Fecal Microbiota Transplantation (hdFMT) BIOLOGICAL

hdFMT (induction) via colonoscopy or oral capsule on C1D1 and C3D1. hdFMT (maintenance) via sigmoidoscopy or oral capsules will be repeated every 9 weeks.

hdFMT + pembrolizumab/lenvatinib (Arm A)

Pembrolizumab DRUG

Pembrolizumab will be administered at 200 mg every 3 weeks (Q3W) as a 30-minute IV infusion (treatment intervals may be increased due to toxicity)

hdFMT + pembrolizumab/lenvatinib (Arm A); pembrolizumab/lenvatinib (Arm B)

Lenvatinib DRUG

Lenvatinib will be administered at 20 mg daily

hdFMT + pembrolizumab/lenvatinib (Arm A); pembrolizumab/lenvatinib (Arm B)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with cutaneous melanoma or unknown primary melanoma may enroll. Patients with uveal or mucosal or acral-lentiginous melanoma are excluded.
• Male participants:
• A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
• Female participants:
• A female participant is eligible to participate if she is not pregnant; not breastfeeding, and at least one of the following conditions applies:
• Not a woman of childbearing potential (WOCBP); OR
• A WOCBP who agrees to follow the contraceptive guidanceper protocol during the treatment period and for at least 120 days after the last dose of study treatment.
• Participants must have progressed on treatment with an anti-PD(L)1 ICI administered either as monotherapy or in combination with other checkpoint inhibitors or other standard/investigational therapies. PD-1 treatment progression is defined by meeting all the following criteria:
• Has received at least 2 doses of an approved anti-PD(L)1 ICI administered as a single agent, in combination with chemotherapy, and/or in combination with other investigational therapy.
• Participants who progressed on/within 3 months of adjuvant therapy with anti-PD(L)1 ICI will eligible.
• Demonstrated disease progression after anti-PD-1/L1 as defined by RECIST v1.1. The initial evidence of PD is to be confirmed by a second assessment no sooner than 4 weeks from the date of the first documented PD.
• Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/anti-PD-L1 mAb.
• NOTE: Progressive disease must be determined as above.
• NOTE: This determination is made by the treating investigator. Once PD is confirmed, the initial date of PD documentation will be considered the date of PD.
• NOTE: Anti-PD(L)1 ICI need not be the most recent line of therapy administered.

You may not qualify if:

• Diagnosis of non-cutaneous melanoma histologies including mucosal melanoma, ocular/choroidal melanoma, and acral-lentiginous melanoma.
• Prior therapies:
• Receipt of prior agent(s) targeting the intestinal microbiome including but not limited to: FMT, defined bacterial consortia, single bacterial species and/or microbiota derived peptides.
• Prior chemotherapy, targeted therapy, and/or small molecule therapy within 2 weeks (or 4 half lives) prior to study Day 1.
• Prior therapy with lenvatinib or other systemic anti-angiogenic therapy.
• Prior radiotherapy within 2 weeks of start of study intervention.
• Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
• A 2-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to disease including CNS disease.
• Contraindications to receiving lenvatinib:
• Has had major surgery within 3 weeks prior to first dose of study interventions.
• NOTE: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility.
• Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
• Has urine protein ≥1 g/24 hours. Note: Participants with proteinuria ≥2+ (≥100 mg/dL) on urine dipstick testing (urinalysis) will undergo 24-hour urine collection for quantitative assessment of proteinuria.
• Has a LVEF below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (TTE).
• Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation.

Sponsors & Collaborators

• Diwakar Davar: lead
• Merck Sharp & Dohme LLC: collaborator
• Gateway for Cancer Research: collaborator

MeSH Terms

Interventions

pembrolizumab; lenvatinib

Study Officials

• Diwakar Davar, MD, PhD

  UPMC Hillman Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine and a Medical oncologist/hematologist

Study Record Dates

• First Submitted: September 1, 2023
• First Posted: September 8, 2023
• Study Start: March 11, 2025
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029
• Last Updated: September 29, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share